title: Common lymphatic endothelial and vascular endothelial receptor-1 mediates the transmigration of regulatory T cells across human hepatic sinusoidal endothelium.
abstract: The common lymphatic endothelial and vascular endothelial receptor (CLEVER-1; also known as FEEL-1 and stabilin-1) is a recycling and intracellular trafficking receptor with multifunctional properties. In this study, we demonstrate increased endothelial expression of CLEVER-1/stabilin-1 at sites of leukocyte recruitment to the inflamed human liver including sinusoids, septal vessels, and lymphoid follicles in inflammatory liver disease and tumor-associated vessels in hepatocellular carcinoma. We used primary cultures of human hepatic sinusoidal endothelial cells (HSEC) to demonstrate that CLEVER-1/stabilin-1 expression is enhanced by hepatocyte growth factor but not by classical proinflammatory cytokines. We then showed that CLEVER-1/stabilin-1 supports T cell transendothelial migration across HSEC under conditions of flow with strong preferential activity for CD4 FoxP3(+) regulatory T cells (Tregs). CLEVER-1/stabilin-1 inhibition reduced Treg transendothelial migration by 40% and when combined with blockade of ICAM-1 and vascular adhesion protein-1 (VAP-1) reduced it by >80%. Confocal microscopy demonstrated that 60% of transmigrating Tregs underwent transcellular migration through HSEC via ICAM-1- and VAP-1-rich transcellular pores in close association with CLEVER-1/stabilin-1. Thus, CLEVER-1/stabilin-1 and VAP-1 may provide an organ-specific signal for Treg recruitment to the inflamed liver and to hepatocellular carcinoma.
authors.affiliation: Centre for Liver Research, University of Birmingham, Edgbaston, Birmingham, United Kingdom B152TT.
authors.forename: Shishir
authors.initials: S
authors.lastname: Shetty
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Weston
authors.forename: Ye H
authors.initials: YH
authors.lastname: Oo
authors.forename: Nina
authors.initials: N
authors.lastname: Westerlund
authors.forename: Zania
authors.initials: Z
authors.lastname: Stamataki
authors.forename: Janine
authors.initials: J
authors.lastname: Youster
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Hubscher
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Lalor
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators; D016201:Receptors, Lymphocyte Homing; C449926:STAB1 protein, human